Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA

Abstract

More than 1,000,000 men undergo prostate biopsy each year in the United States, most for “elevated” serum prostate specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy.

ETS rearrangements in prostate cancer

“…This has important clinical implications, as the TMPRSS2:ERG transcript can be detected in urine and represents a highly specific prostate cancer biomarker. [44][45][46] The common ETS gene fusions are widely believed to have an important oncogenic role, but that ERG or ETV1 overexpression alone is not sufficient to lead to prostate cancer. There is now mounting molecular data for an important concomitant role of TMPRSS2:ERG and the pten/PI3K/ATK pathway activation in prostate cancer oncogenesis.…”

Organ Specific Tumor Markers: What’s New?

“…Prostatic acid phosphatase (PAP) is very useful in monitoring recurrence. Molecular markers such as HER2 amplification [45], expression of the protooncogene BCL-2, [46] and the TMPRSS2-ERG fusion gene [47] remain to be validated and are not currently recommended for routine testing in the NCCN Guidelines. Table 6 gives the prostate cancer markers.…”

Circulating microRNAs: macro-utility as markers of prostate cancer?

“…Prognostic biomarkers that enable differentiation of lethal from indolent forms of cancer would allow individuals to make more informed choices, such as deferring treatment of slow-growing tumors or opting for aggressive treatment of lifethreatening disease. Diagnostic biomarkers that are highly specific to PCa would facilitate better management of men with elevated PSA and/or a positive biopsy, as was recently proposed for urinary TMPRSS2:ERG RNA transcripts (Tomlins et al 2011), or could contradict 'false negative' PSA readings. Finally, it is worth noting that novel biomarkers for PCa are likely to be used in other settings: for example, as indicators to monitor response to novel therapeutic strategies for castration-resistant PCa (CRPCa; see Attard & de Bono (2011) …”